There are at least 8 subtypes of mGluRs in the brain, which have been segregated into three groups. These receptors have predominantly been shown to attenuate glutamate release and modulate normal synaptic transmission in the brain. However, recently evidence suggests that mGluRs expressed in dentate granule cells are also involved in dysfunctional synaptic plasticity after status epilepticus and may contribute to the development of epilepsy. The current proposal is designed to test the hypothesis that the development of hyperexcitability depends specifically upon dysfunctional synaptic inhibition mediated by group III mGluRs. Using selective pharmacological agents and genetically manipulated knockout mice, we will identify a specific mGluR subtype that modulates granule cell excitation of GABAergic interneurons in the dentate. Genomic microarray technology will be used to measure changes in mGluR expression during epileptogenesis. We will also examine mGluR- mediated dysfunction in a chronic model of epilepsy. We expect the results of these studies will lead to an improved understanding of the role of mGluRs in the brain and their possible contribution to epileptogenesis. Further, we anticipate that knowledge gained from this work may also prevent novel treatment strategies for controlling stroke- or trauma-induced brain damage.